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Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(l,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases

a technology of pyrrolidinyl and benzene, which is applied in the field of protacs, can solve the problems of limiting the scope of chemical probes for validating the roles of individual bet targets in physiology and disease, requiring systemic target engagement, and limited the scope of current inhibitors' potential utility as probes

Active Publication Date: 2021-11-23
UNIVERSITY OF DUNDEE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The PROTAC approach achieves selective and efficient degradation of BRD4 over BRD2 and BRD3, providing a safer and more effective therapeutic option while offering tools for validating BET bromodomain proteins as drug targets.

Problems solved by technology

Not only has this prevented the development of BET-inhibitor-based therapies per se, it significantly limits their scope as chemical probes for validating the roles of individual BET targets in physiology and disease.
This lack of intra-BET selectivity has limited the scope for the potential utility of current inhibitors as probes for target validation, particularly due to concerns about potential unwanted side effects or toxicity in a therapeutic setting.
A general limitation associated with conventional occupancy-driven target inhibition approaches is that they often demands systemic target engagement, requiring sustained high concentration of a potent small molecule inhibitor over a prolonged time.
This in turn enhances off-target effects and can lead to unwanted side effects or toxicity in a therapeutic setting.

Method used

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  • Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(l,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases
  • Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(l,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases
  • Derivatives of 1-[(cyclopentyl or 2-pyrrolidinyl)carbonylaminomethyl]-4-(l,3-thiazol-5-yl) benzene which are useful for the treatment of proliferative, autoimmune or inflammatory diseases

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Embodiment Construction

[0056]Described herein is the novel small molecule approach, as developed by the Applicant which uses PROTAC compounds of structure A-L-B, which has been demonstrated to achieve rapid, effective and prolonged intracellular degradation of BET bromodomain proteins. The PROTAC-induced protein degradation potential of the present compounds has been confirmed for binding to VHL, has been demonstrated to be reversed upon blocking proteasome activity, and has been demonstrated to not interfere with the endogenous, physiological levels of VHL and of its natural substrate HIF-1α. Experiments using PROTAC compounds of structure A-L-B, have confirmed that all investigated compounds showed preferential degradation of BRD4 over BRD2 and BRD3 at low concentrations.

[0057]In addition, the downstream gene expression pattern resulting from treatment with a potent and selective PROTAC compound of formula A-L-B, MZ1, has been shown to be similar to JQ1 inhibition for BRD4-dependent genes MYC, P21 and A...

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Abstract

There is provided novel small molecule E3 ubiquitin ligase protein binding ligand compounds, having utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. There is particularly provided PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.

Description

[0001]This application is a National Stage application of International Application No. PCT / GB2016 / 050691 filed Mar. 14, 2016. This application also claims priority under 35 U.S.C. § 119 to GB Patent Application No. 1504314.4, filed Mar. 13, 2015 and GB Patent Application No. 1521858.9, filed Dec. 11, 2015.FIELD OF THE INVENTION[0002]This invention relates to novel small molecule E3 ubiquitin ligase protein binding ligand compounds, and to their utility in PROteolysis Targeted Chimeras (PROTACs), as well as processes for the preparation thereof, and use in medicine. This invention particularly relates to PROTACs which bind to a protein within the bromo- and Extra-terminal (BET) family of proteins, and especially to PROTACs including novel small molecule E3 ubiquitin ligase protein binding ligand compounds which selectively induce degradation of the BRD4 protein within the bromodomain of the BET family of proteins.BACKGROUND OF THE INVENTION[0003]The Bromo- and Extra-terminal (BET) f...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/426A61K31/4025A61K31/4196A61K31/381A61K31/551A61K31/16C07D417/14C07D417/12C07D487/04C07D495/14
CPCA61K31/426A61K31/16A61K31/381A61K31/4025A61K31/4196A61K31/551C07D417/12C07D417/14C07D487/04C07D495/14A61P29/00A61P31/00A61P31/12A61P35/00A61P37/00A61P37/06A61P43/00Y02A50/30
Inventor CIULLI, ALESSIOZENGERLE, MICHAELCHAN, KWOK-HO
Owner UNIVERSITY OF DUNDEE
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